Production of isocarbostyrils

ABSTRACT

ISOCARBOSTYRILS ARE PRODUCED BY HEATING STYRYL ISOCYANATES, MANY OF WHICH ARE NEW COMPOUNDS.

United States Patent 3,663,551 PRODUCTION OF ISOCARBOSTYRILS Antoon M. Deryckere, Uccle, and Fernand J. F. Eloy,

Rhode-Saint-Genese, Belgium, assignors to Union Carbide Corporation N0 Drawing. Filed July 5, 1968, Ser. No. 742,531

Int. Cl. C07d 35/30 U.S. Cl. 260-283 SY 7 Claims ABSTRACT OF THE DISCLOSURE Isocarbostyrils are produced by heating styryl isocyanates, many of which are new compounds.

The invention relates to a process for producing isocarbostyrils by heating a styryl isocyanate. The invention also relates to certain novel styryl isocyanates and isocarbostyrils.

Isocarbostyrils are a known class of compounds having known utility as intermediates in the production of dyes, anti-oxidants, and the like. In addition, isocarbostyrils can be reacted with ethylene oxide to produce surfactants. Various methods have been reported for the production of isocarbostyrils. For instance, Eiden and Nagar, Arch. Pharm., 297, 488 (1964), reported that certain isoclarbostyrils can be produced by heating an N-styryl uret ane:

i c-cllllllcozcilfs A (a) -H 2 s m (Rate tautomer) A limitation in the published results of the Eiden-Nagar synthesis is that R must be an electron-withdrawing group such as -CN, -COOCH or phenyl. Reported attempts to carry out this synthesis when R was hydrogen have been unsuccessful, even when acidic condensing agents (sulfuric acid, phosphorus pentoxide, phosphorus oxychloride) were used--ref., Dey et al., Chem. Abs. 42, 3406 (1948).

Manske et al., I. Am. Chem. Soc., 67, 95 (1945), reported the preparation of 6,7,8-trimethoxy-3,4-dihydroisocarbostyril 'by heating beta-(3,4,S-trimethoxyphenyDethyl isocyanate or its ethyl carbamate ester in the presence of major amounts of phosphorus pentoxide and phosphorus oxychloride condensing agents:

(2:) c 0 2. a A ctr-,0 205 CH 0 3 2001 a can; I ecu; on

en en moo- 11 61130 2 2 cn 0 2 5 3 c11 0 2001. ca e H3 0011 on In one case, the product of a reaction (c) synthesis was dehydrogenated to the corresponding isocarbostyrilref., Anderson et al., J. Am. Pharm. Soc., 41, 643 (1952).

Many other methods for producing isocarbostyrils are known. For instance, isocarbostyrils can be synthesized from (d) isocoumarins, e.g., Ungnade et al., J. Org. Chem, 10, 533 (1945); from (c) homophthalic acid, e.g., Rydon et al., J. Chem. Soc., 1962; 4687; and from (f) phthalaldehydic esters, e.g., King et al., J. Chem. Soc. (1942), 726.

The foregoing methods all have certain disadvantages.

3,663,551 Patented May 16, 1972 ice In method (a), it is reported to be necessary to have an electron-withdrawing group in the alpha-styryl position. Methods (b) and (c) require the use of large proportions of condensing agents to carry out the ring closure reaction, and they require the further step of dehydrogenation in order to produce isocarbostyrils. Methods (d), (e) and (f) are multi-step syntheses from difiiculty available starting reactants. Thus except for unsubstituted isocarbostyril (which can be obtained in one step by treating isoquinoline with alkali), there has been no convenient, economic method for the production of the valuable class of compounds, the isocarbostyrils.

The present invention is based upon the discovery that isocarbostyrils can be produced in good yield by heating styryl isocyanates. The process can be carried out without using any condensing agents, and it is not necessary for the styryl isocyanate to have an electron-withdrawing group in the alpha-styryl position. Economic advantages are also obtained since styryl isocyanates can be synthesized in four convenient steps from readily available benzaldehydes.

The process of the invention can be represented by the following reaction.

The styryl isocyanates that are employed in the invention can be represented by Formula I:

(I) R2 R8 wherein each R individually can be hydrogen, alkyl, alkoxy, halo, two R variables joined together to form a ring which can contain heterocyclic atoms, and the like, provided that at least one R represents hydrogen in a position ortho to the CR =CR NCO moiety, and wherein R and R individually represent hydrogen, alkyl, and the like. Specific illustrative styryl isocyanates that can be used include the following:

styryl isocyanate,

4-methylstyryl isocyanate, Z-methylstyryl isocyanate, 3-methylstyryl isocyanate, 4-ethylstryryl isocyanate, 3-isopropylstyryl isocyanate, 2-butylstyryl isocyanate, 4-pentylstyryl isocyaante, 3-hexylstyryl isocyanate, 4-octylstyryl isocyanate, 4decylstyryl isocyanate, 4-dodecylstyryl isocyanate, 3,4-dirnethylstyryl isocyanate, 2,3,4-trimethylstyryl isocyanate, 3-methoxystyryl isocyanate, 4-methoxystyryl isocyanate, 3,4-dimethoxystyryl isocyanate, 2,3,4-trimethoxystyryl isocyanate, 3,4,5-trimethoxystyryl isocyanate, 3,4-methylenedioxystyryl isocyanate CH=CHNCO 6-isocyanatovinylbenzofuran 2-isocyanatovinylnaphthalene 7-isocyanatovinyl-2H- l-benzopyran CH=CHNCO CII=CHNC O 3-chlorostyryl isocyanate, 4-bromostyryl isocyanate, and the like.

Other useful styryl isocyanates include:

alpha-methylstyryl isocyanate, alpha-butylstyryl isocyanate, 4-methoxy-beta-methylstyryl isocyanate, alpha,- be'ta-dimethylstyryl isocyanate, 4-chloro-beta-methylstyryl isocyanate, and the like.

The preferred styryl isocyanates are those which concyanate, and the like. tain lower alkoxy (i.e., C to C substituents, especially methoxy substituents, chloro substituents, lower alkyl substituents, especially methyl, and those styryl isocyanates which contain a five or six membered oxygenor nitrogen-containing heterocyclic ring fused to the aromatic ring. In general, the R R and R variable individually will contain not more than 18 carbon atoms.

Styryl isocyanates can be produced by known reactions from benzaldehydes, which are readily available starting reactants. The styryl isocyanates wherein R and R are hydrogen can be produced by the following sequence of reactions:

(g) The Knoevenagel-Doebner condensation of aldehydes with malonic acid to form a cinnamic acid-ref., p. 732, Organic Chemistry, Fieser & Fieser, Second ed., D. C. Heath and Company, Boston (1950):

CHO R1 CH2(COOH)2 Pyndme Pipcridine l-GHzCHCOOH CH=CHCOC1 CH=CHCOOH $0012 I 05 (i) Reaction of a cinnamoyl chloride with sodium to produce a cinnamoyl azide-ref, Fieser & Fieser, p. 229:

CH=CHCOC1 a i (j) The Curtious rearrangement of the cinnamoyl azide to a styryl isocyanate-reg., Fieser & Fieser, p. 229:

0 Cl C) Styryl isocyanates wherein R and/ or R are alkyl, can be obtained by the following modifications of the foregoing sequence of reactions:

(k) The Reformatsky reaction of aldehydes or ketones with halogeno esters in the presence of zincref., Fieser & Fieser, page 733:

GH=CHCON3 CH=CHNC O wherein R R and R are as defined above with respect to Formula I. The substituted cinnamic acid is then reacted in accordance with the sequence of reactions (h) through (j).

Other routes to substituted cinnamic acids include:

(1) The Perkin reaction of aldehydes with acid anhydrides in the presence of their corresponding sodium salt Ref., Fieser & Fieser, pp. 730-731:

(R and R are as defined in Formula I):

(m) The Claisen condensation of aldehydes with esters in basic mediumref., Fieser & Fieser, p. 732:

(R and R are as defined in Formula I).

The process of the invention comprises heating a styryl isocyanate at an elevated temperature for a period of time sufiicient to produce an isocarbostyril. If desired, the styryl isocyanate can be produced in situ by heating the corresponding cinnamoyl azide at 6070 C. until evolution of nitrogen ceases, after which the reaction mixture is heated to a higher temperature to effect the ring closure reaction. The exact temperature at which the styryl isocyanate must be heated in order to produce the isocarbostyril is dependent, in part, upon the exact nature of the reactant. In general, however, the reaction occurs at a temperature within the range of from about 200 C. to about 300 C., and preferably from about 220 C. to about 280 C. It is most convenient to carry out the reaction by refiuxing the styryl isocyanate in an inert, liquid reaction medium that boils within the temperature range indicated above. Such reaction mediums include diphenyl ether, the dibutyl ether of diethylene glycol, the acetate ester of the monobutyl ether of diethylene glycol, benzophenone, dimethyl phthalate, and the like. Diphenyl ether is the preferred reaction medium.

The exact reaction time varies to an extent, depending upon the nature of the styryl isocyanate, reaction medium, and reaction temperature. In most cases, the reaction will be completed in from about /2 to about 4 hours, and preferably from about 1 to about 3 hours.

The isocarbostyril can be recovered by conventional procedures. For instance, the reaction medium can be removed by distillation under vacuum, the isocarbostyril can then be dissolved in diethyl ether, and then recrystallized from benzene.

In addition to the utility mentioned above, isocarbostyrils can be used to produce s-triazolo[3,4-a]is0quinolines of known utility (e.g., see U.S. Pat. No. 3,354,164)

(enol tautomer) NHNH:

@- (GHQCO) 90 w The examples which follow illustrate the invention. Unles otherwise stated, parts are by weight and all temperatures are given in centigrade. Compounds that are marked with a superscript have not been reported previously.

in 400 ml. dioxane. After one hour stirring, the mixture is poured out on ice and filtered (M.P.

3-methoxystyryl isocyanate .A solution of 50 g. (0.25 mole) dry acyl azide in 150 ml. dry benzene is refluxed for 8 hours and then evaporated. The residue is distilled under reduced pressure. The isocyanate boils at 120/3 mm. Hg. Yield: 95% from the acid chloride.

6-methoxyisocarbostyril.(a) A solution of 31.8 g. (0.2 mole) styryl isocyanate in 100 ml. diphenyl ether is refluxed for 1 /2 hours. The solvent is evaporated under vacuum and the residue is worked up with ether and filtered. The crude isocarbostyryl is recrystallized from benzene (M.P. 180 yield: 56%) (overall yield-42%).

|(b) Alternatively, a solution of 50 g. (0.25 mole) acyl azide in 150 cc. diphenyl ether is maintained a few hours at until the evolution of nitrogen is terminated. The solution is then refluxed for 1.5 hour and worked up as indicated above in (a).

EXAMPLES 2-10 By procedures analogous to those described in Example 1, a series of isocarbostyrils were prepared from the corresponding benzaldehydes (with Example 8, the cinnamic acid intermediate was prepared as reported by D. Hamer, J. Chem. Soc., 1964, 1847). Table 1, below, displays various physical constants and yields of the intermediates and isocarbostyril products:

TABLE I.SYNTHESIS OF ISOCARBOSIYRILS Cinnamic Isocarbostyrils E Substitueuts acids A, Overall Example (on y l Cinnamoyl Cinnamoyl M.P., Yield, yield, number isocarbostyril) percent chlorides B azldes C Styryl isocyanates D 0. percent percent.

2 7-CH20 93.6 Yield Yield 83% Yield 207 62 41 3--- 7-0113 90 Yield M1. 65 13.1. 90/1 mm. Hg, yield 162 51 34 74% (from B). 4 7-01 73 Yield 98%. MP. 84 B.P. /0.1 mm. Hg,- e 235 69 43, 5

yield 86% (from A). 5 6,7-CHzO1 94 Mil i M.P. 13.1. l1 mm. Hg a 278 1 53. 5 50 1 6 5,6,7-(GH 0) 94 Not purified B Oily crude 13.1. /O.l mm. Hg, 165 81 51. 5

material yield 68% (from A). 7 6,7,8-(OH 0); 80 Yield 95%"... MP. 119 B.P. 139/0.1 mm. Hg, 198 21 10 yield 59% (from A). 8 7-01, 3-611; 50 Not purified M.P. 62 B.P. 85-90/0.1 mm. Hg," u 284 89 35 yield 78% (from A). 9 6,7-(CHa0)g 91.5 ..d0. M.P. 103 *L... B. 130-140/01 mm. Hg," 237 76.6 46

yield 75% (from A). 10 H Yield 86%".-- Ml. 86 Yield 88% from B 212 64 48, 5

1 From A 2 Commercial compound.

a New compound.

EXAMPLE 1 fi-methoxyisocarbostryil 3-methoxycinnamic acid.--Prepared as reported in Sulzbacher et'al., J. Applied Chem. 1, 95 (1951), from 3-methoxybenzaldehyde.

3-methoxycinnamoyl chloride .-A mixture of 89 g. (0.5 mole) 3-methoxycinnamic acid, 130 m1. S001; and 400 ml. dry benzene is refluxed for two hours-and then evaporated under reduced pressure. The residue is distilled under vacuum. The acid chloride distills at 120/1 mm. Hg. The oil solidifies on standing (M.P. 45). Yield: 73%.

3-methoxycinnamoyl azide .39 g. (0.6 mole) Na'N are suspended in a mixture of 68 ml. water and 68 ml. dioxane. -To this mixture cooled at 0 is added slowly a solution containing 64 g. (0.3 mole) of acid chloride In Table II, below, elemental analyses of certain of the isocarbostyril products are displayed:

1 Identical with a sample prepared according to Bischer-Napieralski process (Reaction (0), above, plus dehydrogenation with palladium on carbon).

)Ider)1tical with the compound described by Ungnade (J. 0. Chem. 10 533 Specific identification of the novel intermediate compounds and specific identification of each of the isocarbostyril products of Examples 2-10 are as follows:

EXAMPLE 2 7-methoxyisocarbostyril (known) EXAMPLE 3 4-methylcinnamoyl azide 4-methylstyryl isocyanate 7-methoxyisocarbostyril (known) EXAMPLE 4 4-chlorocinnamoyl azide 4-chlorostyryl isocyanate 7-chloroisocarbostyril (novel) EXAMPLE 5 3,4-methylenedioxycinnamoyl azide 3,4-methylenedioxystyryl isocyanate 1,3-dioxolo [4,5-g] isoquinolin-S-one (novel) EXAMPLE 6 2,3,4-trimethoxycinnamoyl chloride 2,3,4-trimethoxycinnamoy1 azide 2,3,4-trimethoxystyryl isocyanate 5,6,7-trimethoxyisocarbostyril (known) EXAMPLE 7 3,4,5-trimethoxycinnamoyl azide 3,4,5-trimethoxystyryl isocyanate 6,7,8-trimethoxyisocarbostyril (novel) EXAMPLE 8 4-chloro-alpha-methylcinnamoyl chloride 4-chloro-alpha-methylcinnamoyl azide 4-chloro-alpha-methylstyryl isocyanate 7-chloro-3-methylisobarbostyril (novel) EXAMPLE 9 3,4-dimethoxycinnamoyl chloride 3,4-dimethoxycinnamoyl azide 3,4dimethoxystyryl isocyanate 6,7-dimethoxyisocarbostyril (known) EXAMPLE 10 Isocarbostyril (known) EXAMPLE 11 In order to compare the process of the invention with the closest prior art, it was attempted to prepare isocarbostyrils by boiling N-styryl carbamates in diphenyl ether by a procedure analogous to that described in Example 1. The carbamates were prepared from the corresponding cinnamoyl azide by heating with methanol. They had the following structure:

The results of the attempts are shown in Table III, and they are compared with the results found with the corresponding styryl isocyanate:

The significant improvement in yield that is obtained by using the isocyanate rather than the carbamate is immediately obvious. It is also important to remember that the prior art was not aware that the carbamate could be used in the ring closure reaction to produce the isocarbostyril unless there was an electron-withdrawing radical in the alpha position.

Another illustration of the unexpectedly high yield obtained by the process of the invention is found in a comparison with the published results of cyclizing beta-phenethyl isocyanates to 3,4-dihydrocarbostyrils. The betaphenethyl isocyanates that were studied had the formula:

CHzCHzNCO A comparison of the yields obtained is displayed in Table IV.

l Manske et al., Can. J. Research 23B, (1945).

2 Manske et al., J. Can. Chem. Soc. 67-95 (1945). It is pointed out that if it is desired to produce isocarbostyrils by the Manske et a1. synthesis, the additional step of dehydrogenation must be carried out.

EXAMPLE 12 (a) By a procedure analogous to that described in Example 1,5-chloroisocarbostyril was prepared by cyclization of 2-chlorostyryl isocyanate. The 2-chlorostyryl isocyanate was derived ultimately from 2-chlorobenzaldehyde.

(b) 3-butylisocarbostyril was prepared by cyclization of alpha-butylstyryl isocyanate, by a procedure analogous to that described in Example 1.

(c) 4-methylsiocarbostyril was prepared by cyclization of beta-methylstyryl isocyanate by a procedure analogous to that described in Example 1.

What is claimed is:

1. Process which comprises subjecting a styryl isocyanate to an elevated temperature for a period of time sufficient to produce an isocarbostyril, wherein said styryl isocyanate is a compound of the formula:

wherein each R is hydrogen, or wherein not more than 2 R s are selected from the group consisting of methyl, methoxy or ethoxy, provided that at least one R represents hydrogen in a position ortho to the and R and R are linear lower alkyl or hydrogen.

2. The proces s of claim 1 wherein said process is carried out 1n an inert, liquid reaction medium that has a boiling point, at atmospheric pressure, between about 200 and about 300 C.

3. The process of claim 4 wherein the inert, liquid reaction medium is diphenyl ether.

4. Process of claim 1 wherein said temperature is within the range of from about 200 C. to about 300 C.

5. The process of claim 1 wherein said inert, liquid reaction medium is the dibutyl ether of diethylene glycol.

6. The process of claim 1 wherein said process is carried out by refluxing said styryl isocyanate in an inert, liquid reaction medium at a temperature within the range of from about 200 C. to about 300 C.

7. The process of claim 6 wherein said inert, liquid reaction medium is diphenyl ether, the dibutyl ether of diethylene glycol, the acetate ester of the monobutyl ether of diethylene glycol, benzophenone, or dimethyl phthalate.

References Cited UNITED STATES PATENTS 2,538,341 l/l95l Ullyot 260289 3,452,027 6/1969 Sulkowski 260-289 2,647,902 8/1953 Aschner 260-289 3,370,078 2/1968 Bennett 260-453 15 260-283, CN, 288 R, 289 R, 340.5, 345.2, 346.2 R, 

